HIV-1 isolates can be divided into two major subgroups on the basis of their cellular host range in vitro: macrophage (MT) and T-cell line tropic. MT-tropic isolates infect both macrophages and peripheral blood mononuclear cells (PBMC) butare unable to replicate in transformed CD4+ T-cell lines. T-cell line tropic isolates infect both PBMC and CD4+ T- cell lines but replicate poorly or not at all in primary macrophages (MDM). Although T-cells are the major target for HIV-1 replication in peripheral blood, macrophages represent the predominant HIV-1 infected cell type in most tissues. Macrophages are probably the primary reservoir of HIV-1 and may be important for sustaining a persistent infection in individuals for many years. Most HIV-1 isolates we have cloned are T-cell tropic. We have succeeded in obtaining a complete molecular clone from a macrophage-tropic viral isolate. Preliminary biochemical and physical analyses have shown that the spontaneous shedding of the envelope protein(gp120) is drastically different from the typical T-cell line variants. Also the effects of several accessory genes (non-essential in in vitro infections) appear to be dispensable. Mutations in VPU, VPR, or NEF modestly reduced viral replication of the AD8-2 clone in either PBMC macrophages. By comparison with other full-length infectious macrophage-tropic clones of HIV-1, the pAD8-directed HIV-1AD8 stock grew to high titers in cultures of human MDM, as monitored by p24 antigen capture assay. Progeny virion production in HIVAD8-infected primary human macrophages was also readily measurable by the less sensitive reverse transcriptase (RT) assay.